The Integrated Physiological Systems and Pain (IPSP) Core, formerly known as the Integrative Pharmacology Core, provides pharmacological testing, scientific expertise, and related resources to advance research productivity and spark new areas of scientific discovery in substance abuse research. The NIDA P30 Center has a rich history in supporting interdisciplinary projects from established and new investigators, both at Temple University and outside of Temple, that have created synergy among scientists from different disciplines and linked drug addiction research to disorders such as pain and HIV. In this 5-year renewal application, the main themes that will be pursued are: (1) opioids, especially in the context of separating therapeutic (e.g. analgesic) and adverse (e.g. dependence, tolerance, respiratory depression, constipation) effects; (2) interactions between substance abuse and HIV in animal models, especially as related to how psychostimulant and opioid exposure impacts HIV Infectivity, replication, and latency and how HIV infection impacts opioid dependence and analgesia; and (3) crosstalk between neuroimmune and brain reward systems, especially in the context of identifying and characterizing neuroimmune biomarkers (e.g. chemokines, cytokines) of drug addiction and investigating neuroimmune-based therapeutic approaches for substance abuse. Additional emphasis will be placed on supporting drug discovery projects with high translational potential such as characterization of bifunctional NOP-MOP (nociception opioid receptor- mu opioid receptor) agonists, GPR55 ligands, and chemokine receptor antagonists. In terms of prioritizing projects, and aligning with NIH goals of enhancing investigator diversity, efforts will be made to support early career investigators and investigators from populations underrepresented in the biomedical sciences. To expand the impact of NIH-funded research projects related to NIDA's mission through national collaborations, the implementation of innovative methodology is proposed that will enable assessment of three new physiological endpoints: (1) in vivo neuronal activity using miniaturized fluorescence microscopy; (2) respiratory depression for assessment of adverse opioid effects; and (3) chemotherapy-induce neuropathic pain to screen novel experimental compounds for neuroprotective and analgesic efficacy. The expected positive impact of the collaborations proposed by the IPSP Core, through significant interactions with the other Research Support Cores of the NIDA P30 Center, is facilitation of hypothesis-driven, translational research that links drug addiction to pathologies including HIV and pain.